Differential accumulation of secreted AbetaPP metabolites in ocular fluids.

Amyloid-beta (Abeta) accumulates in several types of retinal degeneration and in Alzheimer's disease (AD), but its source has been unclear. We detected the neuronal 695 amino acid form of amyloid-beta protein precursor (AbetaPP) in the normal retina and AbetaPP751 in the retinal pigment epithelium (RPE) and anterior eye tissues. Similar to the brain, alpha- and beta-secretases cleaved AbetaPP to soluble derivatives (sAbetaPP) alpha or beta and membrane-bound C-terminal fragments alpha or beta in the retina and RPE. Levels of sAbetaPP were particularly high in the vitreous and low in aqueous humor revealing a molecular barrier for AbetaPP. In contrast, Abeta40 and Abeta42 levels were only 50% lower in the aqueous than the vitreous humor, indicating relatively barrier-free movement of Abeta. These studies demonstrated a relatively high yield of AbetaPP and Abeta in the ocular fluids, which may serve as a trackable marker for AD. In addition, failure of free clearance from the eye may trigger retina degeneration in a manner similar to Abeta-related neurodegeneration in AD.

[1]  Colin L. Masters,et al.  Amyloid precursor protein processing and retinal pathology in mouse models of Alzheimer’s disease , 2009, Graefe's Archive for Clinical and Experimental Ophthalmology.

[2]  R. Deane,et al.  Clearance of amyloid-β peptide across the blood-brain barrier: Implication for therapies in Alzheimer’s disease , 2009 .

[3]  Marc Tessier-Lavigne,et al.  APP binds DR6 to trigger axon pruning and neuron death via distinct caspases , 2009, Nature.

[4]  E. Mufson,et al.  Beta-amyloid deposition and functional impairment in the retina of the APPswe/PS1DeltaE9 transgenic mouse model of Alzheimer's disease. , 2009, Investigative ophthalmology & visual science.

[5]  J. Pulido,et al.  Chorioretinitis and vitreitis due to Tropheryma whipplei after transplantation: case report and review , 2008, Transplant infectious disease : an official journal of the Transplantation Society.

[6]  K. Ashe,et al.  Amyloid-beta deposits lead to retinal degeneration in a mouse model of Alzheimer disease. , 2008, Investigative ophthalmology & visual science.

[7]  N. Nayak.  Fungal infections of the eye--laboratory diagnosis and treatment. , 2008, Nepal Medical College journal : NMCJ.

[8]  C. B. Rickman,et al.  Targeting age-related macular degeneration with Alzheimer’s disease based immunotherapies: Anti-amyloid-β antibody attenuates pathologies in an age-related macular degeneration mouse model , 2008, Vision Research.

[9]  Pritam Das,et al.  A multigram chemical synthesis of the γ-secretase inhibitor LY411575 and its diastereoisomers , 2007 .

[10]  A. Sillito,et al.  Targeting amyloid-β in glaucoma treatment , 2007, Proceedings of the National Academy of Sciences.

[11]  Fatmire Berisha,et al.  Retinal abnormalities in early Alzheimer's disease. , 2007, Investigative ophthalmology & visual science.

[12]  R. Deane,et al.  Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease. , 2007, Current Alzheimer research.

[13]  R. Kayed,et al.  Drusen deposits associated with aging and age-related macular degeneration contain nonfibrillar amyloid oligomers. , 2006, The Journal of clinical investigation.

[14]  G. Malek,et al.  Apolipoprotein E allele-dependent pathogenesis: a model for age-related retinal degeneration. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[15]  N. Greig,et al.  A partial failure of membrane protein turnover may cause Alzheimer's disease: a new hypothesis. , 2006, Current Alzheimer research.

[16]  J. Hardy,et al.  Has the amyloid cascade hypothesis for Alzheimer's disease been proved? , 2006, Current Alzheimer research.

[17]  S. Ichinose,et al.  The potential role of amyloid beta in the pathogenesis of age-related macular degeneration. , 2005, The Journal of clinical investigation.

[18]  H. Hara,et al.  Vitreous fluid levels of β-amyloid(1–42) and tau in patients with retinal diseases , 2005, Japanese Journal of Ophthalmology.

[19]  P. McMenamin,et al.  An intravital and confocal microscopic study of the distribution of intracameral antigen in the aqueous outflow pathways and limbus of the rat eye. , 2004, Experimental eye research.

[20]  Alexander J. Rivest,et al.  Characterization of β amyloid assemblies in drusen: The deposits associated with aging and age-related macular degeneration , 2004 .

[21]  A. Milam,et al.  Amyloid-beta is found in drusen from some age-related macular degeneration retinas, but not in drusen from normal retinas. , 2003, Molecular vision.

[22]  Qian Sun,et al.  Beta-amyloid secretases and beta-amloid degrading enzyme expression in lens. , 2003, Molecular vision.

[23]  Xudong Huang,et al.  Cytosolic β-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer's disease , 2003, The Lancet.

[24]  P. Frederikse,et al.  Lens defects and age-related fiber cell degeneration in a mouse model of increased AbetaPP gene dosage in Down syndrome. , 2002, The American journal of pathology.

[25]  T. Golde,et al.  A Novel γ-Secretase Assay Based on Detection of the Putative C-terminal Fragment-γ of Amyloid β Protein Precursor* , 2000, The Journal of Biological Chemistry.

[26]  F. D. Miller,et al.  Functional gamma‐secretase inhibitors reduce beta‐amyloid peptide levels in brain , 2000, Journal of neurochemistry.

[27]  D. Selkoe,et al.  Mutagenesis Identifies New Signals for β-Amyloid Precursor Protein Endocytosis, Turnover, and the Generation of Secreted Fragments, Including Aβ42* , 1999, The Journal of Biological Chemistry.

[28]  J. Hardy,et al.  Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1 , 1996, Nature.

[29]  D. Price,et al.  Introduction and expression of the 400 kilobase precursor amyloid protein gene in transgenic mice , 1993, Nature Genetics.

[30]  J. Shioi,et al.  Evidence for intracellular cleavage of the Alzheimer's amyloid precursor in PC12 cells , 1992, Journal of neuroscience research.

[31]  D. Selkoe,et al.  Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. , 1992, Science.

[32]  L. Ozaki,et al.  The barrier function of the posterior capsule. , 1984, Journal - American Intra-Ocular Implant Society.

[33]  N. Greig,et al.  Amyloid and Neurodegeneration: Alzheimer's Disease and Retinal Degeneration , 2009 .

[34]  R. Deane,et al.  Clearance of amyloid-beta peptide across the blood-brain barrier: implication for therapies in Alzheimer's disease. , 2009, CNS & neurological disorders drug targets.

[35]  A. Sillito,et al.  Targeting amyloid-beta in glaucoma treatment. , 2007, Proceedings of the National Academy of Sciences of the United States of America.

[36]  T. Golde,et al.  A multigram chemical synthesis of the gamma-secretase inhibitor LY411575 and its diastereoisomers. , 2007, Bioorganic & medicinal chemistry letters.

[37]  Handbook of Neurochemistry and Molecular Neurobiology: Practical Neurochemistry Methods , 2007 .

[38]  H. Yamashita,et al.  Vitreous fluid biomarkers. , 2006, Advances in clinical chemistry.

[39]  Ronit Nesher,et al.  The pattern electroretinogram in retinal and optic nerve disease , 2004, Documenta Ophthalmologica.

[40]  Alexander J. Rivest,et al.  Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration. , 2004, Experimental eye research.

[41]  C. Masters,et al.  Cytosolic beta-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer's disease. , 2003, Lancet.

[42]  Andreas U Bayer,et al.  Association of glaucoma with neurodegenerative diseases with apoptotic cell death: Alzheimer's disease and Parkinson's disease. , 2002, American journal of ophthalmology.

[43]  Nigel H. Greig,et al.  Advances in the cellular and molecular biology of the beta-amyloid protein in Alzheimer’s disease , 2002, NeuroMolecular Medicine.

[44]  T. Golde,et al.  A novel gamma -secretase assay based on detection of the putative C-terminal fragment-gamma of amyloid beta protein precursor. , 2001, The Journal of biological chemistry.

[45]  D. Selkoe,et al.  Mutagenesis identifies new signals for beta-amyloid precursor protein endocytosis, turnover, and the generation of secreted fragments, including Abeta42. , 1999, The Journal of biological chemistry.

[46]  D. Price,et al.  Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice [corrected]. , 1993, Nature genetics.

[47]  D. Maurice,et al.  The loss of fluorescein, fluorescein glucuronide and fluorescein isothiocyanate dextran from the vitreous by the anterior and retinal pathways. , 1991, Experimental eye research.